Quality by design (QbD) began to gain momentum in the biotechnology industry after FDA published its process analytical technology (PAT) guidance, PAT—A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance in 2004 (1). Global acceptance of QbD and PAT principles are reflected in the contents of the International Conference on Harmonization (ICH) quality guidelines: ICH Q8 Pharmaceutical Development, ICH Q9 Quality Risk Management, and ICH Q10 Pharmaceutical Quality System (2–4). During the past seven years, industry and regulators have devoted significant resources to elucidate a path forward for implementing QbD in the drug-manufacturing environment and toward resolving the various challenges tied to successful implementation (5–8). To date, the first biotech drug application using a QbD approach has yet to be approved by FDA. Still, QbD principles are already being adopted widely throughout the biotechnology industry. This article provides an overview of QbD implementation for the development and commercialization of biologics and follow-on biologics.

QbD's beginnings and cost of implementation

In the traditional approach to biotechnology production, manufacturers define a process and aim to perform the process consistently in a manner that the critical parameters are controlled within a narrow range so as to reduce variability in product quality. This approach has been successfully used to make safe and efficacious biotechnology products for the past few decades. However, because the process controls are fixed in this approach, any variability in raw materials, environmental controls, and/or process operations manifests as variability in product quality and results in lot failures (6–7).

Figure 1: Illustration of key steps in implementation of QbD for a biotech product. Risk assessment and management, raw-material management, and statistical approaches are some of the elements that provide foundational support to the implementation (Ref. 5).

ICH Q8 defines QbD as "a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management" (2). Figure 1 illustrates a roadmap for QbD implementation and outlines the key steps that need to be taken to successfully implement QbD for a biologic drug (5-8).

The current environment, where the cost of healthcare has been recognized to be spiraling out of control, has forced biotechnology companies to become sensitive to the cost of manufacturing their products. It is not surprising then, that when the discussions around QbD first started, cost of implementation was highlighted as a major concern. Today, industry has realized that the benefits of QbD implementation outweigh the startup costs. The biotechnology industry does hope, however, that the approaches taken today to generate the required product and process information, will become more efficient and cost effective.

As demonstrated in Figure 2, the market for these products is expected to pick up in 2012 as a significant number of innovator product patents expire through the year 2017. Expected expiries include Enbrel, Neulasta, Herceptin, Lantus, and Rituxan/Mab Thera. In Europe, a regulatory pathway already exists for follow-on biologics, and 14 such products have been approved (Abseamed, Binocrit, Biograstim, Epoetin-a hexal, Filgrastim hexal, Filgrastim ratiopharm, Nivestim, Omnitrope, Ratiograstim, Retacrit, Silapo, Tevagrastim, Valtropin and Zarzio) (9). A pathway, although approved, is still pending implementation in the United States. Established generic-drug companies, such as Teva Pharmceuticals and Sandoz, are expected to continue to play significant role in development and commercialization of follow-on biologics. At the same time, ewer players based in India and China are expected to emerge as potential follow-on manufacturers. It remains to be seen how companies in less-developed parts of the world will manage the high-cost dynamics of manufacturing these products.